Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS).
Authors: Abdulazeez Salawu, Elizabeth Demicco, Peter W. M. Chung, Jordan Feeney, Erik Spickard, Richa Rathore, Jasmine Lee, Philip Wong, Eoghan Ruadh Malone, Charles Catton, Limore Arones, Madeline J. Phillips, Peter Charles Ferguson, Jay Wunder, Tony Tin, Himanshu Sethi, Minetta C. Liu, David Benjamin Shultz, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2023)

11509 Background: Surgery and (neo)adjuvant radiotherapy (RT) are the mainstay curative treatments for localized STS. Despite treatment, up to 50% of STS patients experience metastatic relapse, and routine use of adjuvant systemic therapy (AST) remains controversial. The presence of ctDNA following curative-intent treatment of STS is a potential biomarker for MRD and may identify patients who are likely to benefit from AST. Given the genomic heterogeneity of STS, a histology-agnostic approach to ctDNA detection in this population is desirable. Methods: Patients (pts) with localized, high risk (size ≥ 5cm, grade ≥ 2) STS were enrolled prior to (neo)adjuvant RT and surgery. Pts who received (neo)adjuvant systemic treatment were excluded. Blood samples for ctDNA analysis were collected at diagnosis, post-RT, post-surgery and every 3 months for up to 2 years. Whole exome sequencing (WES) of archival tumor and matched normal were carried out to identify patient-specific, somatic, single nucleotide variants. Personalized and tumor-informed, multiplex PCR next generation sequencing-based ctDNA (Signatera) assays were then developed to track ctDNA in serially collected plasma samples. ctDNA levels were expressed as mean tumor molecules per milliliter (MTM/ml) of plasma. Radiologic surveillance was performed every 3 months following surgery. The primary endpoint was a ctDNA detection rate of &gt;70% at diagnosis. Secondary endpoints included MRD detection after local therapy and correlation of ctDNA levels with disease relapse. Results: A total of 140 plasma samples from 22 pts [18 male and 4 female; median age: 65 years, range: 30 – 84] were obtained. RT was preoperative in 19/22 pts. Of the 22 tumor samples, 20 had adequate tissue quality for WES to enable ctDNA assay design. Tumor histologic subtypes included undifferentiated pleomorphic sarcoma (n = 6), myxofibrosarcoma (n = 5), and liposarcoma (n = 9). A median of 7 plasma samples per patient (range: 2 – 10) were analyzed. ctDNA was detected in 80% of pts (16/20) at diagnosis, with median ctDNA level of 3.4 MTM/mL (range: 0.2 – 1393.9). Of these 16 pts, 15 (94%) became ctDNA negative at the immediate post-surgical timepoint. In addition, ctDNA was detected in 4 pts (80%) prior to or around radiologic relapse with a median lead time of 92 days. Conclusions: Personalized, tumor-informed ctDNA assays can detect MRD after definitive local therapy and/or prior to radiologic recurrence in patients with localized high-risk STS. As such, serial ctDNA monitoring provides prognostic value and may further identify patients that will benefit from AST treatment. Additional studies evaluating ctDNA as a predictive biomarker for AST benefit are ongoing.